In 1970, marijuana was placed on Schedule 1 of the Drug Enforcement Administration's
controlled-substances list, largely because scientists feared that, like opiates, it had
an extremely high potential for abuse and addiction. But the discovery of THC receptor
sites in the brain refutes that thinking, and may force both scientists and the DEA to
re-evaluate their positions.

Introduction

The next century will view the 1988 discovery of the THC receptor site in the brain as
the pivotal event which led to the legalization of marijuana. Before this discovery, no
one knew for sure just how the psychoactive chemical in marijuana worked on the brain.
Throughout the 1970s and 1980s, researchers made tremendous strides in understanding how
the brain works, by using receptor sites as switches which respond to various chemicals by
regulating brain and body functions. The dominant fear about marijuana in the 20th century
has been that its effects were somehow similar to the dangerously addictive effects of
opiates such as morphine and heroin. Despite widespread decriminalization of marijuana in
the United States in the 1970s, this concern has remained the basis for federal law and
policies regarding the use and study of marijuana. The legal manifestation of this fear is
the continued classification of marijuana as a Schedule I drug, a category shared by
heroin and other drugs that are banned from medical use because of their dangerous,
addictive qualities. While only 11 states have formally decriminalized possession of small
amounts of marijuana, 45 states distinguish between marijuana and other Schedule I drugs
for law-enforcement and sentencing purposes. Until the 1980s, technological limitations
obstructed scientific understanding of the neuropharmacology of THC, of how the active
ingredient in marijuana actually affects brain functions. Observations and conclusions
about this subject, though based on some biological studies, were largely influenced by
observations of behavior. This has allowed cultural prejudice to sustain the faith that
marijuana is somehow related to heroin, and that research will eventually prove this
hypothesis. Actually, the discovery of the THC receptor site and the subsequent research
and observations it has inspired conclusively refute the hypothesis that marijuana is
dope. Many important brain functions which affect human behavior involve the
neurotransmitter dopamine. Serious drugs of abuse, such as heroin and cocaine, interfere
with the brain's use of dopamine in manners that can seriously alter an individual's
behavior. A drug's ability to affect the neural systems related to dopamine production has
now become the defining characteristic of drugs with serious abuse potential.

According to the congressional Office of Technology Assessment, research over the last
10 years has proved that marijuana has no effect on dopamine-related brain systems -
unless you are an inbred Lewis rat (see below), in which case abstention is recommended.
The discovery of a previously unknown system of cannabinoid neural transmitters is
profound. While century-old questions, such as why marijuana is nontoxic, are finally
being answered, new, fascinating questions are emerging - as in the case of all great
discoveries. In the words of Israeli researcher Raphael Mechoulam, the man who first
isolated the structure of THC, "Why do we have cannabinoid receptors?"
Mechoulam's theory will resonate well with marijuana smokers in the United States. He
observes that "Cannabis is used by man not for its actions on memory of movement or
movement coordination, but for its actions on memory and emotions," and asks,
"Is it possible that the main task of cannabinoid receptors . . . (is) to modify our
emotions, to serve as the links which transmit or transform or translate objective or
subjective events into perceptions and emotions?" At a 1990 conference on cannabinoid
research in Crete, Mechoulam concluded his remarks by saying, "Let us hope, however,
that through better understanding of cannabis chemistry in the brain, we may also approach
the chemistry of emotions."

A BRIEF HISTORY OF THC RESEARCH

The receptor breakthrough occurred in 1988 at the St. Louis University Medical School
where Allyn Howlett, William Devane and their associates identified and characterized a
cannabinoid receptor in a rat brain. The breakthrough has a long history leading up to it.
Major figures in American and British organic chemistry, such as Roger Adams, Alex Todd
and Sigmund Loewe, did important work in determining the pharmacology of cannabis in the
1940s and 1950s, but their work ground to a halt due to the disinterest cultivated by the
1937 federal ban on marijuana. While synthetic compounds were created which were close to
the actual compound, THC, they were not equivalent to it. The structure of one related
chemical, cannabidiol, was determined. After repeating the isolation of cannabidiol, in
1963 Mechoulam began work with Yehiel Gaoni that led to the determination of the
biosynthetic pathway by which the plant synthesizes cannabinoids. In 1964 Gaoni and
Mechoulam isolated tetrahydrocannabinol (THC) and a few years later they reported the
first synthesis of THC. Following the identification of the active constituent in
marijuana, scientific research began to fill in the gaps and build on Mechoulam's initial
breakthrough. The neutral and acidic cannabinoids in cannabis were isolated, and their
structures were elucidated. The absolute configurations were determined, as was a
reasonable scheme of biogenesis. Total synthesis of the chemical was obtained, and the
structure-activity relationship was established. These developments laid the foundation
for pharmacological research involving animals and man. This work, along with observations
of marijuana's therapeutic applications, opened up investigation into the medical
properties of cannabinoids in general and THC in particular. Medical research into the
health effects of cannabis also matured throughout this period. In a comprehensive 1986
article in the Pharmacological Review, Leo Hollister of the Stanford University School of
Medicine concluded that "compared with other licit social drugs, such as alcohol,
tobacco and caffeine, marijuana does not pose greater risks." Hollister wondered if
these currently licit drugs would have enjoyed their popular acceptance based on our
current knowledge of them. Nonetheless, it has been widely held throughout the 1980s, as
Hollister concluded, that "Marijuana may prove to have greater therapeutic potential
than these other social drugs, but many questions still need to be answered." The
primary question, though, was how do cannabinoids work on the brain? By 1986, scientists
were already on the slippery slope that would lead to the discovery of the cannabinoid
receptor. The triennial reports from the National Institute on Drug Abuse summarizing
research on marijuana had begun to omit references to research on marijuana-related brain
damage and instead focus on brain receptor research. A comprehensive article by Renee Wert
and Michael Raoulin was published in the International Journal of the Addictions that
year, detailing the flaws in all previous studies that claimed to show brain damage
resulting from marijuana use. As Hollister independently concluded, "Brain damage has
not been proved." The reason, obviously, is that the brain was prepared in some
respects to process THC. Also in 1986, Mechoulam put together a book reviewing this
research, Cannabinoids as Therapeutic Agents (CRC Press, Boca Raton, FL). One promising
area of research was the use of cannabinoids as analgesics or painkillers. A synthetic
cannabinoid named CP 55,940, 10-100 times more potent than THC, was also developed in
1986; this was the key to the cannabinoid receptor breakthrough. Receptors are binding
sites for chemicals in the brain, chemicals that instruct brain cells to start, stop or
otherwise regulate various brain and body functions. The chemicals which trigger receptors
are known as neurotransmitters. The brain's resident neurotransmitters are known as
endogenous ligands. In many instances, drugs mimic these natural chemicals working in the
brain. Scientists are just now confirming their determinations as to which endogenous
ligands work on the cannabinoid receptors; it is likely that the neurotransmitter which
naturally triggers cannabinoid receptors is one known as anandamide. Research continues.
To grossly oversimplify the research involved, a receptor is determined by exposing brain
tissue to various chemicals and observing if any of them uniquely bind to the tissue. The
search for a cannabinoid receptor depended on the use of a potent synthetic that would
allow observation of the binding. CP 55,940 provided this potency, and it allowed Howlett,
Devane and their associates, working with tissue from a rat brain, to fulfill precise
scientific criteria for determining the existence of a pharmacologically-distinct
cannabinoid in brain tissue. A year later the localization of cannabinoid receptors in
human brains and other species was determined by scientists at the National Institute of
Mental Health, led by Miles Herkenham and including Ross Johnson and Lawrence Melvin, who
had worked with Howlett and Devane on the earlier study.

RECEPTORS IN THE BRAIN

The locations of the cannabinoid receptors are most revealing of the way THC acts on
the brain, but the importance of this determination is best understood in comparison with
the effects of other drugs on the brain. Neurons are brain cells which process
information. Neurotransmitter chemicals enable them to communicate with each other by
their release into the gap between the neurons. This gap is called the synapse. Receptors
are actually proteins in neurons which are specific to neurotransmitters, and which turn
various cellular mechanisms on or off. Neurons can have thousands of receptors for
different neurotransmitters, causing any neurotransmitter to have diverse effects in the
brain. Drugs affect the production, release or re-uptake (a regulating mechanism) of
various neurotransmitters. They also mimic or block actions of neurotransmitters, and can
interfere with or enhance the mechanisms associated with the receptor. Dopamine is a
neurotransmitter which is associated with extremely pleasurable sensations, so that the
neural systems which trigger dopamine release are known as the "brain reward
system." The key part of this system is identified as the mesocorticolimbic pathway,
which links the dopamine-production area with the nucleus of accumbens in the limbic
system, an area of the brain which is associated with the control of emotion and behavior.
Cocaine, for example, blocks the re-uptake of dopamine so that the brain, lacking
biofeedback, keeps on producing it. Amphetamines also block the re-uptake of dopamine, and
stimulate additional production and release of it. Opiates activate neural pathways that
increase dopamine production by mimicking opioid-peptide neurotransmitters which increase
dopamine activity in the ventral tegmental area of the brain where the neurotransmitter
originates. Opiates work on three receptor sites, and in effect restrain an inhibitory
amino acid, gamma-aminobutyric acid, that otherwise would slow down or halt dopamine
production. All of these substances can produce strong reinforcing properties that can
seriously influence behavior. The rewarding properties of dopamine are what accounts for
animal studies in which animals will forgo food and drink or willingly experience electric
shocks in order to stimulate the brain reward system. It is now widely held that drugs of
abuse directly or indirectly affect the brain reward system. The key clinical test of
whether a substance is a drug of abuse potential or not is whether administration of the
drug reduces the amount of electrical stimulation needed to produce self-stimulation
response, or dopamine production. This is an indication that a drug has reinforcing
properties, and that an individual's use of the drug can lead to addictive and other
harmful behavior. To be precise, according to the Office of Technological Assessment
(OTA): "The capacity to produce reinforcing effects is essential to any drug with
significant abuse potential." Marijuana should no longer be considered a serious drug
abuse because, as summarized by the OTA: "Animals will not self-administer THC in
controlled studies . . . . Cannabinoids generally do not lower the threshold needed to get
animals to self-stimulate the brain regard system, as do other drugs of abuse."
Marijuana does not produce reinforcing effects. The definitive experiment which measures
drug-induced dopamine production utilizes microdialysis is live, freely-moving rats. Brain
microdialysis has proven that opiates, cocaine, amphetamines, nicotine and alcohol all
affect dopamine production, whereas marijuana does not. This latest research confirms and
explains Hollister's 1986 conclusion about cannabis and addiction: "Physical
dependence is rarely encountered in the usual patterns, despite some degree of tolerance
that may develop." Most important, the discoveries of Howlett and Devane, Herkenham
and their associates demonstrate that the cannabinoid receptors do not influence the
dopamine reward system.

CANNABINOID RECEPTORS Research has enabled scientists to know which portions of the
brain control various body functions, and this knowledge has been used to explain the
pharmacological properties of drugs that activate receptor sites in the brain. There is a
dense concentration of cannabinoid binding sites in the basal ganglia and the cerebellum
of the base-brain, both of which affect movement and coordination. This discovery will aid
in determining the actual physical mechanism by which THC affects spasticity and provides
therapeutic benefits to patients with multiple sclerosis and other spastic disorders.
While there are cannabinoid receptors in the ventromedial striatum and basal ganglia which
are areas associated with dopamine production, no cannabinoid receptors have been found in
dopamine-producing neurons, and as mentioned above, no reinforcing properties have been
demonstrated in animal studies. There is one study by Gardner and Lowinson, involving
inbred Lewis rats, in which doses of THC lowered the amount of electrical stimulation
required to trigger the brain reward system. However, no one has been able to replicate
the results with any other species of rat, or any other animal. The finding is believed to
be the result of some inbred genetic variation in the inbred species, and is both widely
mentioned in the literature and disregarded. According to Herkenham and his associates,
"There are virtually no reports of fatal cannabis overdose in humans. The safety
reflects the paucity of receptors in medullary nuclei that mediate respiratory and
cardiovascular functions." This is also why cannabinoids have great promise as
analgesics or painkillers, in that they do not depress the function of the heart or the
lungs. In this respect, they are far superior to opiates, which decrease the entire
physiological system because the receptors are all over the medulla as well as the brain.
Marijuana is distinguished from most other illicit drugs by the locations of its
brain-receptor sites for two predominant reasons: (1) The lack of receptors in the medulla
significantly reduces the possibility of accidental, or even deliberate, death from THC,
and (2) the lack of receptors in the mesocorticolimbic pathway significantly reduces the
risks of addiction and serious physical dependence. As a therapeutic drug, these features
are God's greatest gifts.

THE CHEMISTRY OF EMOTIONS

Mechoulam regrets that more has not been done in the therapeutic application of THC. In
a 1986 interview with the International Journal of the Addictions, he said that,
"Knowing what I know today, I would have worked more on the therapeutic aspects of
cannabis. This area apparently needs a major push that is has not had up till now,
particularly given that it has a therapeutic potential. One of the reasons that it has not
been pushed was than most pharmaceutical companies years ago were afraid to get into that
field. Companies were 'burnt' working on amphetamines and LSD. . . . They are afraid of
notoriety." Clearly, cannabis acts on coordination of movement by way of the
receptors in the cerebellum and basal ganglia, and on memory by way of the receptors in
the limbic system's hippocampus, which "gates" information during memory
consolidation. Mechoulam believes that in humans these actions "are rather
marginal." "Cannabis," he states, "is used . . . for its actions on
mood and emotion." The key to understanding the reason for the presence of
cannabinoid receptors in the human brain lies in understanding the role of the receptors
in the limbic system, which has a central role in the mechanisms which govern behavior and
emotions. The limbic system coordinates activities between the visceral base-brain and the
rest of the nervous system. "We know next to nothing on the chemistry of
emotions," Mechoulam instructs. It is his hope that future research on the role of
cannabinoid receptors in the brain will shed light on this new area of investigation and
reflection.

THE FUTURE OF MARIJUANA LAWS

Advances in neurobiology are redefining the scientific basis for addiction. These
advances have important ramifications for addiction treatment, and for the treatment of
numerous organic diseases and conditions. More importantly for marijuana users, these
advances in neurobiology will ultimately force changes in the law. The law is constantly
being modified in response to technological changes. The passage of the Controlled
Substances Act in 1972 was in part due to a greater understanding of drug abuse brought
about by the medical research of the time. The law instituted a policy by which regulation
and criminal penalties regarding controlled substances were to be correlated with the
harmfulness of the substance. Specifically, the law lists the "actual or relative
potential for abuse" as the first matter to be considered in determining the
appropriate scheduling of a drug. Schedule I is for drugs which have a "high
potential for abuse." While the scheduling of marijuana and its subsequent
availability for research and medical use was the subject of a 22-year unsuccessful court
battle spearheaded by the National Organization for the Reform of Marijuana Laws, the
question of marijuana's abuse potential was never addressed during the litigation and
related proceedings. The suit over medical marijuana sought to reschedule marijuana as a
Schedule II drug, which also implies a "high potential for abuse." This made the
abuse question irrelevant to the court proceedings. However, the abuse question is the
pre-eminent issue in attempts to reform marijuana laws, and it is the weak link upon which
the entirety of marijuana prohibition rests. The most recent research indicates that
marijuana does not have a high potential for abuse, especially relative to other scheduled
drugs such as heroin, cocaine, sedatives and amphetamines. The medical-marijuana petition
was rejected by the administrator of the DEA because of the lack of scientific studies
detailing marijuana's medical value. The court appeal essentially concerned whether or not
this was a reasonable standard in light of the government's historic disinterest in
funding such studies. While courts have ruled that DEA can rely on research studies, or
the lack thereof, in its decision-making about the scheduling of marijuana, they have not
ruled on the actual issues which determine the proper legal scheduling of marijuana. The
discovery of cannabinoid receptor sites, and their relevance to the understanding of the
pharmacology of THC in the brain, provides the basis for a new challenge to the legitimacy
of marijuana's Schedule I status, a pivotal event in marijuana's eventual legalization.